Changes in infant microbiome linked to prenatal opioids
Authors: Roxanne Nelson
Journal: The Lancet Microbe (2022)

Prenatal exposure to opioids has been linked to adverse effects on fetal development, including preterm birth, stillbirth, possible congenital defects, and neurobehavioural changes. It is also associated with a risk for neonatal abstinence syndrome and neonatal opioid use disorder. However, data now suggest that opioid exposure may affect the infant's microbiome and, in turn, trigger neurological or behavioural effects later in life. Using a mouse model, researchers identified significant changes to the infant gut microbiome associated with maternal exposure to oxycodone. These changes were associated with alterations in metabolic pathways, suggesting that maternal opioid use influences the metabolism of infants. The preclinical study, published in mSystems, is the first to demonstrate that in-utero exposure to an opioid drug can lead to long-term effects on the gut microbiota. “As mice and humans have comparable gut microbiota populations, the findings likely translate to humans and are of potential concern,” study author Cheryl Rosenfeld (University of Missouri, Columbia, MO, USA) told The Lancet Microbe. The length of exposure needed to disrupt the microbiome in humans remains unclear, however, in the study, the mice received oxycodone prior to breeding and then daily thereafter throughout gestation, but exposure can vary dramatically in pregnant women. “At the present time, we are not able to determine if reduced consumption of oxycodone and similar drugs might lead to less harmful effects on the fetus and gut microbiota,” said Rosenfeld. “However, short exposure to hydromorphone on days 11–13 was sufficient to induce gut dysbiosis in mouse dams and their newborn offspring.” Rosenfeld noted that it would also be of interest to examine development windows of exposure. “The fetus is presumably at the greatest risk as organ systems, including those of the gastrointestinal and neural systems, are being launched,” she said. “In the case of gut microbiota, they might also be susceptible at the onset of parturition when the maternal microbiome seeds and colonises the infant gut.” For obvious ethical reasons, a randomised clinical trial could not be conducted in pregnant women, but as an alternative, the microbiome of infants exposed to opioids could be studied, explained Rosenfeld. “It is also important though, at this time, to establish long-term epidemiological studies on linking perinatal exposure to opioid drugs and changes in gut microbiota and overall health throughout the lifespan.” Opioid analgesics are commonly prescribed to pregnant women in the USA, and exposure to these agents may adversely affect the gastrointestinal tract and slow gut motility, alter gut permeability, and affect the gut microbiome. Although these drugs might also affect gut microbiome in infants, there have been no studies to date that have determined if developmental exposure to opioids will result in long term health consequences, and correspondingly on host responses. The researchers hypothesised developmental exposure to oxycodone would induce gut dysbiosis and that these bacterial changes would be associated with adult neurobehavioural and metabolic changes. To test this hypothesis, female mice received a daily dose of 5 mg/kg of oxycodone or saline solution for 2 weeks before breeding and then throughout the gestation period. Faecal matter was collected from the mouse pups at 120 days of age in both the experimental and control groups, and bacterial DNA was isolated from the samples. The pups were also tested with an array of behavioural and metabolic tests, and response to oxycodone exposure differed between male and female offspring. Male mice showed higher abundances of Coriobacteriaceae, Roseburia spp, Sutterella spp, and Clostridia than the control group. In female mice, relative abundance of Butyricimonas spp, Bacteroidetes, Anaeroplasma spp, TM7, Enterococcus spp, and Clostridia was higher in the oxycodone group than controls. Bacterial changes were also associated with predictive metabolite pathway alterations that also varied according to sex. In pups of both sexes, affected gut microbiota was associated with metabolic but not behavioural alterations. “I think this is really interesting, but unknown whether it would be cause for concern in humans,” commented Stephanie Merhar (Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA). “The gut microbiota can be affected by many different things in humans, such as caesarean section versus vaginal delivery, or breastmilk versus formula feedings. Some differences in the microbiome don't seem to have much clinical relevance.” Merhar pointed out that it is unclear if the gut microbiota has been studied in opioid-exposed versus unexposed babies. “Obviously you could not randomise but you could try to find a unexposed control group with similar demographics to the exposed group, especially ensuring that a similar proportion of babies in each group were born by caesarean section versus vaginal delivery and were breastfed versus formula fed but it would be difficult to study this in a rigorous fashion in humans,” said Merhar. For the study on the effect of oxycondone on gut microbiota see mSystems 2022; 7: e0033622